CN103724376A - Novel latent antitumor drug platinum complex and preparation method thereof - Google Patents
Novel latent antitumor drug platinum complex and preparation method thereof Download PDFInfo
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- CN103724376A CN103724376A CN201310750875.9A CN201310750875A CN103724376A CN 103724376 A CN103724376 A CN 103724376A CN 201310750875 A CN201310750875 A CN 201310750875A CN 103724376 A CN103724376 A CN 103724376A
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Abstract
The invention relates to the technical field of platinum complexes, and in particular relates to a latent platinum (II) complex with antitumor activity and a preparation method thereof. The platinum (II) complex, which takes 2,2'-dipyridyl and 1,10'-phenanthroline as auxiliary ligand and 4-[(3-ethynyl phenyl) amino]-quinazolo [6,7-b]-12-crown-4 as main ligand, can be used as a novel latent antitumor drug. The latent antitumor drug platinum complex disclosed by the invention, compared to clinical platinum substances such as cis-platinum and the like, has equal and even better antitumor activity, and simultaneously reserves antitumor advantages of icotinib hydrochloride, thus providing a new way for development and application o the platinum drugs.
Description
Technical field
The present invention relates to platinum complexes technical field, refer more particularly to platinum (II) title complex of the concrete antitumour activity of a class potentiality and preparation method thereof.
Background technology
At present, tumour is the great killer of human life's health, is one of mankind's difficult medical problem of urgently capturing, the World Health Organization (WHO) issue, the new cancer patient 1,000 ten thousand in the whole world in 2000, existing cancer stricken patient 2,240 ten thousand; Predict the year two thousand twenty, population in the world 8,000,000,000, the new patient 2,000 ten thousand of cancer, existing cancer stricken case will reach 3,000 ten thousand; The cancer morbidity of China is also in continuous increase.
EGF-R ELISA (EGFR) is a kind of multi-functional glycoprotein being distributed widely on each cell membranes in tissue of human body, it is the growth factor receptors family of numerous protein Tyrosylprotein kinase, research shows that it plays a crucial role in the generation of the many cancers of the mankind and development, exists high expression level or the unconventionality expression of EGFR in many noumenal tumours glucagonomas such as () mammary cancer, bladder cancer, lung cancer, a cancer, cancer of the stomach.
EGFR kinase inhibitor is at molecular biology and be proved to be clinically good antitumous effect.At present, for clinical EGFR kinase inhibitor, mainly contain Gefitinib, Tarceva, Ah handkerchief for Buddhist nun, Conmana etc.Wherein, hydrochloric acid Conmana (Kai Meina, Zhejiang Bei Da pharmaceutcal corporation, Ltd) be China first there is the small molecules target anticancer new drug of independent intellectual property right, it is effective to advanced Non-small cell lung, has overcome the shortcomings such as traditional chemotherapy poor specificity, toxic side effect be large.
Meanwhile, platinum-containing anticancer drug is also indispensable medicine in cancer chemotherapy.At present, clinical medicinal platinum class material has cis-platinum, carboplatin, oxaliplatin, S 254, Eptaplatin, lobaplatin etc.Although can have result for the treatment of to kinds cancer for clinical platinum-containing anticancer drug, also all have the intrinsic shortcoming of many medicines itself: large, the antitumor spectrum of toxic side effect is narrow, resistance etc.
Summary of the invention
The object of the invention is to overcome prior art deficiency, design and synthesize a kind of novel platinum (II) kind anti-cancer drugs thing, expectation retains the anticancer advantage of hydrochloric acid Conmana, meanwhile, can overcome the narrow deficiency that waits of platinum-containing anticancer drug side effect and antitumor spectrum.
Technical solution of the present invention is:
Serial platinum (II) title complex, is characterized in that, with 2,2 '-dipyridyl, 1,10 '-phenanthroline is co-ligand; With 4-[(3-ethynyl phenyl) amino]-quinazo [6,7-b]-12-crown-4 is main part, so formed the novel platinum of following formula (II) title complex:
Wherein L is 2,2 '-dipyridyl, 1,10 '-phenanthroline.
Novel platinum (II) title complex, is characterized in that having following structure:
Novel platinum of the present invention (II) title complex A chemoattractant molecule formula is [Pt (bpy) (C
44h
40n
6o
8)], molecular weight is 1132.1; Platinum (II) complex B molecular formula is [Pt (phen) (C
44h
40n
6o
8)], molecular weight is 1156.1.
The preparation method of platinum of the present invention (II) title complex, comprises the following steps:
(1) first with K
2ptCl
4for raw material, with 2,2 '-dipyridyl (or 1,10 '-phenanthroline) by amount of substance ratio, be 1: 1, at 85 ℃-90 ℃, react 4～6h; After processing, obtain cis-[Pt (bpy) Cl
2] (or cis-[Pt (phen) Cl
2]).
(2) at Ar gas, protect; under CuI katalysis; take 30mL methylene dichloride and diisopropylamine mixed solution (v/v=1: 1) be solvent; with 4-[(3-ethynyl phenyl) amino]-quinazo [6; 7-b]-12-crown-4 (Icotinib) is raw material, cis-[Pt (bpy) Cl obtaining with step (1)
2] (or cis-[Pt (phen) Cl
2]) under 40 ℃ of conditions, react 24～36h.
(3) utilize underpressure distillation evaporate to dryness methylene dichloride and diisopropylamine, then product processing being obtained is placed in beaker, adds methylene dichloride-water (25mL-25mL), more under agitation drips 25% ammoniacal liquor, until powder all dissolves, water dichloromethane extraction, merges organic phase, and organic phase is with after distilled water wash, with the anhydrous sodium sulfate drying of about 5g, spend the night, second day, removes by filter sodium sulfate, and vacuum rotary steam is removed methylene dichloride.
(4) step (3) is processed to the alumina chromatographic column separation for thick product obtaining, be then spin-dried for eluent, obtain powdery product and be product.
The reaction of step (2) is in the protection of Ar gas, under CuI katalysis, take methylene dichloride and diisopropylamine mixed solution as solvent (v/v=1: 1), react 24～36h under the condition that temperature is 40 ℃.
Raw material Icotinib in step (2) and cis-[Pt (bpy) Cl
2] mol ratio be 2: 1;
Raw material Icotinib in step (2) and cis-[Pt (phen) Cl
2] mol ratio be 2: 1;
In step (2), Catalysts Cu I used and the mol ratio of platinum (II) are 1: 1;
Eluent described in step (4) is mixed by a certain percentage by methyl alcohol and methylene dichloride.
Novel platinum (II) title complex expectation prepared by the present invention has the equal even more superior anti-tumor activity of the platinum class materials such as cis-platinum with application clinically, remain with the anticancer advantage of hydrochloric acid Conmana, this has opened up a new way for the Application and Development of platinum medicine simultaneously.
Accompanying drawing explanation
Fig. 1 is the present invention [Pt (bpy) (C
44h
40n
6o
8)] it
1hNMR spectrogram;
Fig. 2 is the present invention [Pt (bpy) (C
44h
40n
6o
8)] MALDI-MS spectrogram;
Fig. 3 is the present invention [Pt (bpy) (C
44h
40n
6o
8)] it
13c NMR spectrogram;
Fig. 4 is the present invention [Pt (phen) (C
44h
40n
6o
8)] it
1hNMR spectrogram;
Fig. 5 is the present invention [Pt (phen) (C
44h
40n
6o
8)] MALDI-MS spectrogram.
Embodiment
As Figure 1-Figure 5, below in conjunction with embodiment, the present invention is described in detail.
Embodiment mono-
Novel platinum (II) title complex A's is synthetic
1, in 50mL tri-neck round-bottomed flasks, add K
2ptCl4 (3mmol, 1245.3mg), then add minimal amount of water to make K
2ptCl4 dissolves completely, is heated closely and boils afterwards; , 2,2 '-dipyridyl (3mmol, 468.6mg) is dissolved in minimum ethanol meanwhile, then under magnetic agitation, it is dropwise joined to the K closely boiling
2ptCl
4in the aqueous solution; Drip and finish, heating reflux reaction 4～6h at 85 ℃～90 ℃, after precipitation is all separated out, naturally cools to room temperature, and suction filtration is with frozen water, ethanol, ether washing, dry.Obtain yellow-green colour powder cis-[Pt (bpy) Cl
2], productive rate 80%
2, under the provide protection of Ar gas, by cis-[Pt (bpy) Cl
2] (0.4mmol, 168.9mg), 4-[(3-ethynyl phenyl) amino]-quinazo [6,7-b]-12-crown-4 (0.8mmol, 313.1mg), CuI (0.4mmol, 76.2mg) be placed in 100mL tri-neck round-bottomed flasks, then add 30mL methylene dichloride and diisopropylamine (v/v=1: mixed solvent 1), magnetic agitation is heated to 40 ℃, reaction 24～36h, obtains brown solution.
3, utilize underpressure distillation evaporate to dryness methylene dichloride and diisopropylamine, then product processing being obtained is placed in beaker, adds methylene dichloride-water (25mL-25mL), more under agitation drips 25% ammoniacal liquor, until powder all dissolves, water dichloromethane extraction, merges organic phase, and organic phase is with after distilled water wash, with the anhydrous sodium sulfate drying of about 5g, spend the night, second day, removes by filter sodium sulfate, and vacuum rotary steam is removed methylene dichloride.
4, step (3) is processed to the alumina chromatographic column separation for thick product obtaining, eluent is ethanol/methylene (v: v=1: 50), be then spin-dried for eluent, obtain yellow-green colour powder platinum (II) title complex A, productive rate 32%.
Data characterization result is as follows:
1H?NMR(400MHz，DMSO)δ9.62(d，J＝5.1Hz，2H)，9.40(s，2H)，8.72(d，J＝7.9Hz，2H)，8.52(s，2H)，8.45(t，J＝8.0Hz，2H)，8.15(s，2H)，7.93(dd，J＝13.9，7.3Hz，4H)，7.74(d，J＝8.1Hz，2H)，7.35-7.26(m，4H)，7.15(d，J＝7.5Hz，2H)，4.29(s，8H)，3.80(s，4H)，3.74(s，4H)，3.64(s，8H).
13C?NMR(101MHz，DMSO)δ?157.01，156.49，156.37，153.89，150.51，150.16，148.00，140.58，139.78，128.70，128.56，126.80，125.04，124.50，119.82，112.15，110.70，110.22，101.47，89.85，73.38，70.93，70.82，70.45，69.26，68.88.MALDI-MS?for?A:calcd.1132.1[M]+，found1132.3[M]
+.
Embodiment bis-
Synthesizing of novel platinum (II) complex B
1, in three neck round-bottomed flasks, add K
2ptCl
4(2mmol, 830.2mg), then add minimal amount of water to make K
2ptCl4 dissolves completely, is heated closely and boils afterwards; , 1,10 '-phenanthroline (2mmol, 360.4mg) is dissolved in minimum ethanol meanwhile, then under magnetic agitation, it is dropwise joined to the K closely boiling
2in the PtCl4 aqueous solution, drip and finish, heating reflux reaction 4～6h at 85 ℃～90 ℃, after precipitation is all separated out, naturally cools to room temperature, and suction filtration, washes with frozen water, ethanol, ether, dry.Obtain yellow-green colour powder cis-[Pt (phen) Cl
2], productive rate 82%.
2, under the provide protection of Ar gas, by cis-[Pt (phen) Cl
2] (0.8mmol, 357.0mg), 4-[(3-ethynyl phenyl) amino]-quinazo [6,7-b]-12-crown-4 (1.6mmol, 626.2mg), CuI (0.8mmol, 152.4mg) be placed in 100mL tri-neck round-bottomed flasks, then add 30mL methylene dichloride and diisopropylamine (v/v=1: mixed solvent 1), magnetic agitation is heated to 40 ℃, reaction 24～36h, obtains brown solution.
3, utilize underpressure distillation evaporate to dryness methylene dichloride and diisopropylamine, then product processing being obtained is placed in beaker, adds methylene dichloride-water (25mL-25mL), more under agitation drips 25% ammoniacal liquor, until powder all dissolves, water dichloromethane extraction, merges organic phase, and organic phase is with after distilled water wash, with the anhydrous sodium sulfate drying of about 5g, spend the night, second day, removes by filter sodium sulfate, and vacuum rotary steam is removed methylene dichloride.
4, step (3) is processed to the alumina chromatographic column separation for thick product obtaining, eluent is ethanol/methylene (v: v=1: 30), be then spin-dried for eluent, obtain yellow-green colour powder platinum (II) complex B, productive rate 38%.
Data characterization result is as follows:
1H?NMR(400MHz，DMSO)δ9.86(d，J＝5.0Hz，2H)，9.42(s，2H)，9.08(d，J＝8.2Hz，2H)，8.53(s，2H)，8.34(s，2H)，8.27(dd，J＝8.2，5.3Hz，2H)，8.17(s，2H)，7.95(s，2H)，7.76(d，J＝8.1Hz，2H)，7.34(t，J＝7.9Hz，2H)，7.29(s，2H)，7.21(d，J＝7.5Hz，2H)，4.30(s，8H)，3.80(s，5H)，3.74(s，4H)，3.64(s，8H).MALDI-MS?for?B:calcd.1156.1[M]
+，found1157.3[M]
+.
Claims (6)
1. serial platinum (II) title complex, is characterized in that, with 2,2 '-dipyridyl, 1,10 '-phenanthroline is co-ligand; With 4-[(3-ethynyl phenyl) amino]-quinazo [6,7-b]-12-crown-4 is main part, so formed the novel platinum of following formula (II) title complex:
Wherein L is 2,2 '-dipyridyl, 1,10 '-phenanthroline.
2. according to described platinum (II) title complex of claim 1, it is characterized in that, wherein said compound has following formula structure:
3. according to the platinum of claim 1 (II) title complex, it is characterized in that, wherein said compound has following formula structure:
4. obtain a preparation method for platinum claimed in claim 1 (II) title complex, it is characterized in that: the method comprises the following steps:
(1) first take K2PtCl4 as raw material, with 2,2 '-dipyridyl by amount of substance ratio, be 1: 1, at 85 ℃～90 ℃, react 4～6h; After processing, obtain cis-[Pt (bpy) Cl
2];
(2) in protection of inert gas; under CuI katalysis; take methylene dichloride and diisopropylamine mixed solution (v/v=1: 1) be solvent; with 4-[(3-ethynyl phenyl) amino]-quinazo [6; 7-b]-12-crown-4 (Icotinib) is raw material, cis-[Pt (bpy) Cl obtaining with step (1)
2] under 40 ℃ of conditions, react 24～36h;
(3) utilize underpressure distillation evaporate to dryness methylene dichloride and diisopropylamine, then product processing being obtained is placed in beaker, adds methylene dichloride-water (25mL-25mL), more under agitation drips 25% ammoniacal liquor, until powder all dissolves, water dichloromethane extraction, merges organic phase, and organic phase is with after distilled water wash, with anhydrous sodium sulfate drying, spend the night, second day, removes by filter sodium sulfate, and vacuum rotary steam is removed methylene dichloride;
(4) step (3) is processed to the alumina chromatographic column separation for thick product obtaining, be then spin-dried for eluent, obtain powdery product and be product.
5. obtain a preparation method for platinum claimed in claim 1 (II) title complex, it is characterized in that: the method comprises the following steps:
(1) first take K2PtCl4 as raw material, with 1,10 '-phenanthroline by amount of substance ratio, be 1: 1, at 85 ℃～90 ℃, react 4～6h; After processing, obtain cis-[Pt (phen) Cl
2];
(2) in protection of inert gas; under CuI katalysis; take methylene dichloride and diisopropylamine mixed solution (v/v=1: 1) be solvent; with 4-[(3-ethynyl phenyl) amino]-quinazo [6; 7-b]-12-crown-4 (Icotinib) is raw material, cis-[Pt (phen) Cl obtaining with step (1)
2] under 40 ℃ of conditions, react 24～36h;
(3) utilize underpressure distillation evaporate to dryness methylene dichloride and diisopropylamine, then product processing being obtained is placed in beaker, adds methylene dichloride-water (25mL-25mL), more under agitation drips 25% ammoniacal liquor, until powder all dissolves, water dichloromethane extraction, merges organic phase, and organic phase is with after distilled water wash, with anhydrous sodium sulfate drying, spend the night, second day, removes by filter sodium sulfate, and vacuum rotary steam is removed methylene dichloride;
(4) step (3) is processed to the alumina chromatographic column separation for thick product obtaining, be then spin-dried for eluent, obtain powdery product and be product.
6. the application of platinum claimed in claim 1 (II) title complex in preparing antitumor drug.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891769A (en) * | 2010-06-18 | 2010-11-24 | 河北大学 | Anti-tumor platinum complexes |
| WO2013064128A1 (en) * | 2011-10-31 | 2013-05-10 | 浙江贝达药业有限公司 | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891769A (en) * | 2010-06-18 | 2010-11-24 | 河北大学 | Anti-tumor platinum complexes |
| WO2013064128A1 (en) * | 2011-10-31 | 2013-05-10 | 浙江贝达药业有限公司 | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
Non-Patent Citations (1)
| Title |
|---|
| BINGRAN YU ET AL.: "Synthesis and characterization of a luminescence metallosupramolecular hyperbranched polymer", 《CHEM. COMMUN.》 * |
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Application publication date: 20140416 |